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Bupropion Inhibits Serotonin Type 3AB Heteromeric Channels at Clinically Relevant Concentrations

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Bupropion Inhibits Serotonin Type 3AB Heteromeric Channels at Clinically Relevant Concentrations 1521-0111/97/3/171–179$35.00 https://doi.org/10.1124/mol.119.118349 MOLECULAR PHARMACOLOGY Mol Pharmacol 97:171–179, March 2020 Copyright ª 2020 by The Author(s) This is an open access article distributed under the CC BY-NC Attribution 4.0 International license. Bupropion Inhibits Serotonin Type 3AB Heteromeric Channels at Clinically Relevant Concentrations Antonia G. Stuebler and Michaela Jansen Department of Cell Physiology and Molecular Biophysics and Center for Membrane Protein Research, School of Medicine, Texas Tech University Health Sciences Center, Lubbock, Texas Received September 25, 2019; accepted December 13, 2019 Downloaded from ABSTRACT Bupropion, a Food and Drug Administration–approved antide- bupropion was reversible and time-dependent. Of note, prein- pressant and smoking cessation aid, blocks dopamine and cubation with a low concentration of bupropion that mimics norepinephrine reuptake transporters and noncompetitively therapeutic drug conditions inhibits 5-HT–induced currents in 5- inhibits nicotinic acetylcholine and serotonin (5-HT) type 3A HT3A and 5-HT3AB receptors considerably. In summary, we receptors (5-HT3ARs). 5-HT3 receptors are pentameric ligand- demonstrate that bupropion inhibits heteromeric 5-HT3ABRs as gated ion channels that regulate synaptic activity in the central well as homomeric 5-HT3ARs. This inhibition occurs at clinically molpharm.aspetjournals.org and peripheral nervous system, presynaptically and postsynap- relevant concentrations and may contribute to bupropion’s tically. In the present study, we examined and compared the clinical effects. effect of bupropion and its active metabolite hydroxybupropion SIGNIFICANCE STATEMENT on mouse homomeric 5-HT3A and heteromeric 5-HT3AB recep- tors expressed in Xenopus laevis oocytes using two-electrode Clinical studies indicate that antagonizing serotonin (5-HT) voltage clamp experiments. Coapplication of bupropion or type 3AB (5-HT3AB) receptors in brain areas involved in mood hydroxybupropion with 5-HT dose dependently inhibited 5- regulation is successful in treating mood and anxiety disor- HT–induced currents in heteromeric 5-HT type 3AB receptors ders. Previously, bupropion was shown to be an antagonist at (5-HT3ABRs) (IC50 5 840 and 526 mM, respectively). The homopentameric 5-HT type 3A receptors. The present work corresponding IC50s for bupropion and hydroxybupropion for provides novel insights into the pharmacological effects that at ASPET Journals on September 24, 2021 homomeric 5-HT3ARs were 10- and 5-fold lower, respectively bupropion exerts on heteromeric 5-HT3AB receptors, in partic- (87 and 113 mM). The inhibition of 5-HT3ARs and 5-HT3ABRs was ular when constantly present at low, clinically attainable non–use dependent and voltage independent, suggesting concentrations. The results advance the knowledge on the bupropion is not an open channel blocker. The inhibition by clinical effects of bupropion as an antidepressant. Introduction peripheral nervous system (Thompson and Lummis, 2013) and are involved in virtually all brain functions (Hassaine The 5-hydroxytryptamine-3, or serotonin (5-HT) type 3, et al., 2014). receptor is an ionotropic receptor and a member of the Cys- To date, five different 5-HT3 subunits have been identified loop family of pentameric ligand-gated ion channels, and (5-HT3A – 5-HT3E).Thefirstsubunittobecloned,5-HT3A thereby, differs from G-protein-coupled serotonin receptors (Maricq et al., 1991), is the only subunit among these that can (Thompson and Lummis, 2007). The 5-HT type 3 receptor (5- form functional homo-oligomeric receptors on the cell mem- HT3R) is similar in structure and function to other members of brane when expressed in Xenopus oocytes or cell lines (Hussy the pentameric ligand-gated ion channel family, including et al., 1994). Introduction of the 5-HT3B subunit yields cation-selective nicotinic acetylcholine (nACh) receptors functional heteromers with altered properties compared with (nAChRs) and anion-selective GABAA and glycine receptors. the homo-oligomer and with heteromer function more closely Malfunction in these receptors has been linked to several resembling the functional responses observed in native neurologic disorders (Lemoine et al., 2012). Together, they tissues (Hussy et al., 1994; Davies et al., 1999). When compared are responsible for fast neurotransmission in the central and with 5-HT3A, the 5-HT type 3AB receptor (5-HT3ABR) differs in agonist concentration-response curves, shows increased single- channel conductance and desensitization, and an altered Research reported in this publication was supported in part by the National Institute of Neurologic Disorders and Stroke of the National Institutes of current-voltage relationship (Davies et al., 1999; Dubin Health [R01 NS077114 (to M.J.)]. The content is solely the responsibility of the et al., 1999; Kelley et al., 2003b). authors and does not necessarily represent the official views of the National Institutes of Health. The 5-HT3R is widely distributed in the central and https://doi.org/10.1124/mol.119.118349. peripheral nervous systems and on extraneuronal cells, such ABBREVIATIONS: 5-HT, serotonin; 5-HT3R, 5-HT type 3 receptor; 5-HT3AR, 5-HT type 3A receptor; 5-HT3ABR, 5-HT type 3AB receptor; Bup, bupropion; cRNA, complementary RNA; EC30, concentration that elicits approximately 30% of the maximal response; HydroB, hydroxybupropion; nACh, nicotinic acetylcholine; nAChR, nACh receptor; OR-2, oocyte ringer solution. 171 172 Stuebler and Jansen as monocytes, chondrocytes, T-cells, and synovial tissue (Fiebich et al., 2004). In the periphery, 5-HT3Rs are found in the autonomic, sensory, and enteric nervous systems (Faerber et al., 2007), where they are involved in regulating gastroin- testinal functions, such as motility, emesis, visceral percep- tion, and secretion (Niesler et al., 2003; Lummis, 2012). The highest density of 5-HT3Rs in the central nervous system is in the hindbrain, particularly the dorsal vagal complex involved in the vomiting reflex, and in limbic structures, notably the amygdala, hippocampus, nucleus accumbens, and striatum (Jones et al., 1992; Miyake et al., 1995). Substantial 5-HT3B expression was identified in the human brain with high levels in the amygdala, hippocampus, and the nucleus caudate (Dubin et al., 1999; Tzvetkov et al., 2007). A high amount of 5-HT3Rs are found on presynaptic nerve fibers (Nayak et al., 2000; Miquel et al., 2002), through which they can modulate the release of other neurotransmitters, such as Downloaded from dopamine, cholecystokinin, GABA, substance P, and acetyl- choline (Chameau and van Hooft, 2006; Faerber et al., 2007). Fig. 1. Comparing 5-HT3ARs to 5-HT3ABRs. (A) Sample traces of 5-HT3A (black) and 5-HT3AB (green) at varying concentrations of 5-HT. (B) Owing to its involvement in many brain functions, the 5-HT3R Concentration-response curves show a higher potency of 5-HT at 5-HT3ARs represents an attractive therapeutic target. as compared with 5-HT3AB, as well as a steeper Hill slope. Parameters from 5 m 5 6 5 5-HT3R antagonists are used to effectively treat patients these curves: 5-HT3A:EC50 0.8 M, nH 2.53 0.58, n 5, 5-HT3AB: 5 m 5 6 5 molpharm.aspetjournals.org experiencing irritable bowel syndrome and chemotherapy-/ EC50 4.30 M, nH 1.04 0.02, n 8. Data are represented as the mean 6 S.D. (C) Direct comparison of 5-HT3A and 5-HT3AB inward current radiotherapy-induced and postoperative nausea and vomiting evoked by 1 mM 5-HT for 30 seconds. (Thompson and Lummis, 2007). Some antidepressants (Choi et al., 2003; Eisensamer et al., 2003) and antipsychotic drugs prepared in distilled water. Hydroxybupropion (100 mM, Toronto (Rammes et al., 2004) also antagonize 5-HT Rs, which, 3 Research Chemicals, Inc., North York, Canada) was dissolved in DMSO. together with other preclinical and clinical studies, suggests All solutions were made in oocyte ringer solution (OR-2) immediately the relevance of 5-HT3R antagonism for treating psychiat- before conducting experiments. ric disorders (Walstab et al., 2010; Bétry et al., 2011). We Molecular Biology. Complementary DNA encoding the mouse recently discovered that bupropion (Bup), another antide- 5-HT3AR (AAT37716) containing a V5-tag (GKPIPNPLLGLDSTQ) pressant, antagonizes 5-HT type 3A receptors (5-HT3ARs) close to the N-terminus (Jansen et al., 2008) and the mouse 5-HT3B at ASPET Journals on September 24, 2021 (Pandhare et al., 2017). receptor (NP_064670) in the pGEMHE vector were used for oocyte Bupropion was first approved as an “atypical” antidepressant expression (Reeves et al., 2001). Plasmids were linearized with the over 30 years ago, and today it is one of the most commonly NheI restriction enzyme and in vitro transcribed with the T7 RNA prescribed antidepressants. Despite its recognized clinical polymerase kit (mMESSAGE mMACHINE T7 Kit; Applied Bio- systems/Ambion, Austin, TX). Capped complementary RNA (cRNA) efficacy for both depression and smoking cessation, a com- was purified with the MEGAclear Kit (Applied Biosystems/Ambion) prehensive picture of how bupropion modulates neurotrans- and precipitated using 5 M ammonium acetate. cRNA dissolved in ’ mission is still emerging. Bupropion s therapeutic effect is nuclease-free water was stored at 280°C. thought to be mediated by the blocked reuptake of dopamine X. laevis Oocyte Preparation. Oocytes were isolated, enzymat- and norepinephrine (Stahl et al., 2004) and the noncompet- ically defolliculated, and stored as previously described (Goyal et al., itive inhibition
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